Hepatocyte Growth factor/scattering factor (HGF/SF) is a pleiotropic cytokine that performs various functions in developmental processes. HGF/SF binds to its receptor c-Met tyrosine kinase to induce various bioreactions including the migration, invasion, proliferation, survival and morphological change of target cells (Jiang et al., Critical Reviews in Oncology/Hematology. 53:35-69, 2005). HGF/SF is a cytokine of mesenchymal origin and was reported to act on hepatocytes and other epithelial cells including endothelial cells, melanocytes, hematopoietic cells and osteocytes, to activate the above reactions through its receptor c-Met (Tamagnone and Comoglio, Cytokine & Growth factor Rev. 8:129-142, 1997).
The present inventors previously reported that the deregulation of HGF/SF-Met signaling does not influence the usual function of hepatocytes, but adversely affects the regeneration of damaged hepatocytes. Since then, the present inventors confirmed that, when the skin in addition to the liver is damaged, HGF/SF and c-Met are secreted. In other words, large amounts of HGF/SF and c-Met are secreted from hyperproliferative skin tissue to promote the proliferation of skin cells. However, it was reported that c-Met is found in the skin and hair follicles, whereas HGF/SF is usually expressed only in hair follicles and is found in skin that is damaged. Thus, HGF/SF remains in an inactivated state until the skin is damaged, and it is activated around wounds after the skin is damaged (Journal of Cell Biology 177(1):151-162, 2007). Accordingly, it is known that HGF/c-Met directly regulates skin regeneration and repair (Nakamura et al., Nature. 342:440-443, 1993; Huh et al., Proc Natl Acad Sci USA. 101:4477-4482, 2004).
In vitro and in vivo studies indicated that HGF/SF also acts on the nervous system, and many studies on the function of HGF/SF to protect motor neurons were reported (Novak et al., Journal of Neuroscience. 20:326-337, 2000). In addition, it was suggested that HGF/SF plays an important role in defensive physiological mechanisms following general organ damage such as heart damage (Nakamura et al., J Clin Invest. 106:1511-1519, 2000). Indeed, it was demonstrated that the HGF/MET pathway is involved in the processes of neural infraction, progressive nephritis, liver cirrhosis and pulmonary fibrosis and that HGF is overexpressed in lesions of such degenerative diseases to exhibit a defensive physiological activity of protecting tissue from damage (Comoglio et al., Nature Review Drug Discovery. 7:504-516, 2008).
Therefore, it has been suggested that HGF/SF can be developed as an agent for preventing the death of neural cells in the central nervous system, an agent for treating neurodegenerative diseases, including Parkinson's disease, ischemia leading to nervous infarction and Alzheimer's disease, and a regenerative therapeutic agent that is used after the occurrence of damage to the heart, the kidneys, the liver and the lungs, as well as ulcerative wounds.
The excessive activity of HGF/c-Met signaling is associated with tumorigenesis of various endothelial cells and angiogenesis, and from this point of view, it was suggested that an antagonistic c-Met antibody that targets c-Met can be used as an anticancer agent (Comoglio et al., Nature Review Drug Discovery. 7:504-516, 2008). For example, it was reported that a one-armed c-Met antibody efficiently inhibits tumor growth in a transplanted mouse model by negatively regulating the activation of HGF caused by dimerization of c-Met (Jin et al, Cancer Research 68(11): 4360-4368, 2008; Comoglio et al., Nature Review Drug Discovery. 7:504-516, 2008). In addition, in T-cell therapy, an antibody to an antigen that is overexpressed in cancer cells is used in tumor targeting for linking of T cells in the genetic manipulation of T cells that selectively recognizes a cancer cell surface antigen (Sadelain, The Cancer Journal 15(6):451-455, 2009). However, it was not reported that agonistic antibodies against c-Met can be used as alternatives for anticancer agents.
Meanwhile, the cytotoxic drug doxorubicin that is used as an anticancer agent, and the like, targets the cell cycle, and thus the toxicity thereof is dependent on the proliferation of cancer cells. Also, these drugs are used in the highest acceptable amounts to provide clinical therapeutic effects. However, it has been reported that such anticancer agents merely kill rapidly proliferating cells, cannot distinguish normal cells from cancer cells or cancer tissues to kill cells other than cancer cells, and cause side effects such as vomiting when being used at high concentrations. In addition, these anticancer agents can cause resistance to anticancer agents when being used for a long period of time. For these reasons, there is an urgent need for an improved therapy in which a cytotoxic drug targets and kills only cancer cells. In addition, conventional drugs have a disadvantage in that their therapeutic effects are reduced in hypoxic tumor conditions in which the level of oxygen decreases as a tumor grows.